English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Biallelic  PNKP  variants cause heterogeneous disorders ranging from neurodevelopmental disorder with microcephaly/seizures to adult-onset Charcot–Marie–Tooth disease. To date, only postnatal descriptions exist. We present the first prenatal diagnosis of  PNKP -related primary microcephaly. Pathological examination of a male fetus in the 18th gestational week revealed micrencephaly with extracerebral malformations and thus presumed syndromic microcephaly. A recessive disorder was suspected because of previous pregnancy termination for similar abnormalities. Prenatal trio-exome sequencing identified compound heterozygosity for the  PNKP  variants c.498G&gt;A, p.[(=),0?] and c.302C&gt;T, p.(Pro101Leu). Segregation confirmed both variants in the sister fetus. Through RNA analyses, we characterized exon 4 skipping affecting the  PNKP  forkhead-associated (FHA) and phosphatase domains (p.Leu67_Lys166del) as the predominant effect of the paternal c.498G&gt;A variant. We retrospectively investigated two unrelated individuals diagnosed with biallelic  PNKP -variants to compare prenatal/postnatal phenotypes. Both carry the splice donor variant c.1029+2T&gt;C  in  trans  with a variant in the FHA domain (c.311T&gt;C, p.(Leu104Pro); c.151G&gt;C, p.(Val51Leu)). RNA-seq showed complex splicing for c.1029+2T&gt;C and c.151G&gt;C. Structural modeling revealed significant clustering of missense variants in the FHA domain with variants generating structural damage. Our clinical description extends the  PNKP -continuum to the prenatal stage. Investigating possible  PNKP -variant effects using RNA and structural modeling, we highlight the mutational complexity and exemplify a  PNKP -variant characterization framework.

Prenatal phenotype of PNKP-related primary microcephaly associated with variants affecting both the FHA and phosphatase domain